Analgesic compositions

ABSTRACT

The present invention provides compositions useful in reducing or preventing pain in a subject in need thereof. In one embodiment, the compositions comprise a halogenated volatile compound. The present invention further includes a method of reducing or preventing pain in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of the invention. Dosing regimens contemplated within the invention include one-time administration, continuous administration or periodic administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of, and claims priority to,U.S. patent application Ser. No. 16/564,649, filed Sep. 9, 2019, nowallowed, which is a continuation of, and claims priority to, U.S. patentapplication Ser. No. 15/971,781, filed May 4, 2018, now U.S. Pat. No.10,507,189, which is a continuation of, and claims priority to U.S.patent application Ser. No. 15/585,932, filed May 3, 2017, now U.S. Pat.No. 10,071,065, which is a divisional of, and claims priority to, U.S.patent application Ser. No. 14/775,584, filed Sep. 11, 2015, now U.S.Pat. No. 9,655,867, which is a 35 U.S.C. § 371 national phaseapplication from, and claims priority to, International Application No.PCT/US2014/028169, filed Mar. 14, 2014, which claims priority under 35U.S.C. § 119(e) to U.S. Provisional Application No. 61/814,485, filedApr. 22, 2013 and No. 61/792,383, filed Mar. 15, 2013, all of whichapplications are hereby incorporated by reference in their entiretiesherein.

BACKGROUND OF THE INVENTION

Pain is defined as an unpleasant sensory and emotional experience.Millions of people suffer from pain, ranging from minor headaches todebilitating chronic pain. Acute pain may be associated with a medicalprocedure or injury. Chronic pain may be associated with conditions suchas cancer, HIV or diabetes. Currently available drugs used to treat painhave significant associated adverse effects, such as nausea, vomiting,tolerance, constipation, dyspepsia, myocardial infarction, stroke andchemical dependence.

An analgesic (also known as a painkiller) is the general name for a drugused to relieve pain (achieve analgesia). Analgesic drugs act throughvarious mechanisms on the peripheral and central nervous systems. Theyinclude paracetamol (p-acetylamino phenol, also known as acetaminophen);the non-steroidal anti-inflammatory drugs (NSAIDs), such as thesalicylates; opioid drugs, such as morphine and opium; and drugs forlocalized analgesia/anesthesia, such as lidocaine and benzocaine.Analgesics are distinct from general anesthetics, which reversiblyrender a patient unconscious and unaware of the surroundings. Localanesthesia leads to loss of feeling, whereas analgesia decreases thesensation of pain.

In choosing analgesics, the severity and response to medicationdetermines the choice of compound. The WHO pain ladder, originallydeveloped in cancer-related pain, is widely applied to find suitablecompounds in a stepwise manner (Cancer pain relief and palliative care:Report of a WHO expert committee (1990). World Health OrganizationTechnical Report Series, 804. Geneva, Switzerland: World HealthOrganization, pp. 1-75). The choice of analgesic is also determined bythe type of pain: traditional analgesics are less effective forneuropathic pain, and classes of drugs not normally consideredanalgesics, such as tricyclic antidepressants and anticonvulsants(Dworkin et al., 2003, Arch. Neurol. 60 (11):1524-34), may bebeneficial. For certain types of pain, such as pain associated withmedical procedures or injury, localized analgesic effects may beimportant.

Venous access procedures, such as blood draws and IV starts, are aroutine part of medical practice. These procedures are also the sourceof a considerable amount of pain and distress, particularly amongchildren who require regular injections and/or venous access. Concernabout the effect of such pain on children has been the focus ofconsiderable study by the American Academy of Pediatrics (AAP), whichdevoted an entire supplement of Pediatrics on the issue (November 2008).As a result, the AAP and American Pain Society (APS) have adoptedguidelines recommending the use of localized anesthetics to treat suchpain whenever possible.

Pain associated with venous access procedures is not only the mostcommon cause of pain in hospitalized children but also the second mostcommon cause of “worst pain”. Pediatric inpatients report IV lineplacement as the leading cause of procedure-related pain in thehospital, on par with postsurgical pain. Venipuncture causes not onlymoderate or severe pain in a significant number of pediatric inpatients,but also elevated levels of pre-procedural and procedural distress.Young children, even neonates, have highly refined pain-sensing systems.Continuous exposure to such pain can cause maladaptive pain response asan adult, but also the painful memory of such events can havesignificant psychological and physiological ramifications on laterpainful episodes.

Thus, considerable attention has been focused on the issue of preventingor reducing venous access pain in children. In fact, national andinternational organizations have proposed clinical guidelinesrecommending the use of local anesthetics in such cases, and suchguidelines have been included in the hospital-accreditation process.Unfortunately, compliance with these guidelines is low. One of the majorbarriers to implementing the guidelines is the slow onset of action andresultant treatment delays associated with existing medications.

Currently, there is no pain medication that alleviates pain associatedwith minor procedures quickly, cost-effectively, and topically. Currentpharmaceutical products are virtually all based on lidocaine, whileother local anesthetics cannot easily penetrate intact human skin andcannot be used on large areas. Lidocaine-based creams take 45-60 minutesto begin taking effect, reaching maximum effect at about 120 minutes,and this slow onset limits their use in clinical settings.

Further, current topical analgesics' slow onset of action impedes theiruse for treating other procedural pain, such as that associated withpainful cosmetic and medical dermatological procedures (for example moleremoval, skin biopsies, Botox and fillers, aesthetic injections), withmedical injections (such as immunizations, and insulin administration),with circumcision, heel sticks and other minor medical procedures aswell as with non-medical uses (such as tattoos, tattoo removal andpiercings).

An inhalational anesthetic possesses general anesthetic properties andcan be delivered via inhalation. Inhalational anesthetics areadministered by anesthetists through an anesthesia mask, laryngeal maskairway or tracheal tube connected to some type of anesthetic vaporizerand an anesthetic delivery system. Non-limiting examples of inhalationalanesthetics include volatile anesthetics (such as isoflurane,sevoflurane, desflurane or aliflurane) and anesthetic gases (such asnitrous oxide or xenon).

Volatile anesthetics share the property of being liquid at roomtemperature, but evaporating easily for administration by inhalation.They are hydrophobic (i.e., as liquids, they are not freely misciblewith water, and as gases they dissolve in oils better than in water).The ideal volatile anesthetic offers smooth and reliable induction andmaintenance of general anesthesia with minimal effects on other organsystems. In addition, it is odorless or pleasant to inhale; safe for allages and in pregnancy; not metabolized; rapid in onset and offset;potent; and safe for exposure to operating room staff. It is also cheapto manufacture; easy to transport and store, with a long shelf life;easy to administer and monitor with existing equipment; stable to light,plastics, metals, rubber and soda lime; non-flammable andenvironmentally safe. None of the volatile anesthetics currently in useare ideal, although many have some of the desirable characteristics. Forexample, sevoflurane is pleasant to inhale, rapid in onset/offset, andsafe for all ages, but expensive and approximately half as potent asisoflurane. The full mechanism of action of volatile anesthetics isunknown and has been the subject of intense debate (Travis, 2004,Science News (July 3^(rd))).

There exists a need in the art for novel compositions that provideefficacious pain management for subjects in need thereof. Thesecompositions should display good analgesic properties with minimal sideeffects or risks. These compositions should provide analgesia to asubject without compromising the subject's motor functions. Thesecompositions should have manageable volatility, be chemically stable,and miscible and formulated with commercially acceptable excipients. Fortopical applications these compositions should penetrate human skin,preferably rapidly, and their effect should last for enough time toallow the performance of appropriate procedures. The present inventionfulfills this need.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the invention provides a composition comprising ahalogenated volatile compound and at least one component selected fromthe group consisting of: an alcohol; 2-(2-ethoxyethoxy)-ethanol; apolyol; an organic solvent; an organic carbonate; hydroxypropylcellulose (HPC); a fatty acid or a salt thereof; a polyethylene glycol(PEG); a polyethyne glycol (PPG); a monoester of a (methyl vinylether-maleic acid) co-polymer; a copolymer of2-(2-hydroxypropoxy)propan-1-ol (PPG-12) and 1-methylenebis-4-isocyanatocyclohexane (SMDI); a poloxamer; saccharine, and anycombinations thereof. In another aspect, the invention provides a methodof reducing or preventing pain in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a composition of the invention, whereby pain in the subject isreduced or prevented. In yet another aspect, the invention provides amethod of dressing a wound in a subject in need thereof, the methodcomprising applying to the wound a therapeutically effective amount of acomposition of the invention.

In certain embodiments, the halogenated volatile compound is selectedfrom the group consisting of isoflurane, halothane, enflurane,sevoflurane, desflurane, methoxyflurane, and any mixtures thereof. Inother embodiments, the composition comprises about 5% to about 95% w/whalogenated volatile compound. In yet other embodiments, the compositioncomprises about 50% to about 90% w/w halogenated volatile compound.

In certain embodiments, the alcohol is selected from the groupconsisting of methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, t-butanol, and any mixtures thereof. In otherembodiments, the composition comprises about 2% to about 20% w/walcohol. In yet other embodiments, the alcohol is ethanol and thecomposition comprises about 8.25%, about 10%, about 10.5%, about 12.5%,about 14.25%, about 15%, or about 20% w/w ethanol.

In certain embodiments, the composition comprises about 5% or about 10%w/w 2-(2-ethoxyethoxy)-ethanol.

In certain embodiments, the polyol is selected from the group consistingof ethylene glycol, propylene glycol, glycerol, and any mixturesthereof. In yet other embodiments, the composition comprises about 5% toabout 20.25% w/w polyol. In yet other embodiments, the compositioncomprises about 5%, about 8%, about 14.75%, about 15%, about 15.25% orabout 20.25% w/w polyol.

In certain embodiments, the organic solvent is selected from the groupconsisting of dimethylsulfoxide (DMSO), dimethylisosorbide, and anymixtures thereof. In other embodiments, the composition comprises fromabout 5% to about 50% w/w organic solvent. In yet other embodiments, thecomposition comprises from about 10% to about 50% w/w organic solvent.

In certain embodiments, the organic carbonate is selected from the groupconsisting of propylene carbonate, ethylene carbonate and any mixturesthereof. In other embodiments, the composition comprises about 2.5% w/worganic carbonate.

In certain embodiments, the HPC comprises HPC GF, HPC MF or any mixturesthereof. In other embodiments, the composition comprises from about 1%to about 5% w/w HPC. In yet other embodiments, the composition comprisesabout 1.75%, about 2%, about 2.25%, about 2.5%, or about 5% w/w HPC.

In certain embodiments, the fatty acid or salt thereof is selected fromthe group consisting of myristoleic acid, palmitoleic acid, sapienicacid, oleic acid, elaidic acid, vaccenic acid, linoleic acid,linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoicacid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, cerotic acid, and any combinationsthereof. In other embodiments, the composition comprises from about 1%to about 5% w/w fatty acid or a salt thereof. In yet other embodiments,the composition comprises about 3% w/w fatty acid or a salt thereof.

In certain embodiments, the PEG is selected from the group consisting ofPEG-200, PEG-300, PEG-400, PEG-600, PEG-[950-1,050], PEG-1,000,PEG-[1,300-1,600], PEG-[1,305-1,595], PEG-1,450, PEG-1,500, PEG-2,000,PEG-2,050, PEG-3,000, PEG-[3,000-3,700], PEG-3,350, PEG-4,000,PEG-4,600, PEG-6,000, PEG-8,000, PEG-10,000, PEG-12,000, PEG-20,000,PEG-35,000, and any mixtures thereof. In other embodiments, thecomposition comprises about 6% to about 78% w/w PEG. In yet otherembodiments, the composition comprises about 6%, about 9%, about 10%,about 15%, about 18.25%, about 20%, about 20.5% or about 78% PEG.

In certain embodiments, the monoester of a (methyl vinyl ether-maleicacid) co-polymer is n-butyl, isopropyl, ethyl, or any mixtures thereof.In other embodiments, the composition comprises from about 15% to about20% w/w monoester of a (methyl vinyl ether-maleic acid) co-polymer. Inyet other embodiments, the composition comprises about 20% w/w monoesterof a (methyl vinyl ether-maleic acid) co-polymer.

In certain embodiments, the composition comprises from about 5% to about15% w/w copolymer of PPG-12 and SMDI. In other embodiments, thecomposition comprises about 10% w/w copolymer of PPG-12 and SMDI.

In certain embodiments, the composition comprises about 2% w/wsaccharine.

In certain embodiments, the composition comprises about 15% to about 20%w/w PPG.

In certain embodiments, the composition comprises from about 1% to about5% w/w poloxamer. In other embodiments, the poloxamer comprisespoloxamer 188, poloxamer 407, and any mixtures thereof.

In certain embodiments, the composition is selected from the groupconsisting of: (a) about 50% w/w DMSO, and about 50% w/w isoflurane(201, FIGS. 1A-1B); (b) about 28% w/w DMSO, about 10% w/w copolymer ofPPG-12 and SMDI, about 2% w/w HPC GF, and about 60% w/w isoflurane (202,FIGS. 1A-1B); (c) about 25% w/w DMSO, about 5% w/w HPC GF, and about 70%w/w isoflurane (203, FIGS. 1A-1B); (d) about 3% w/w oleic acid, about14.75% w/w propylene glycol, about 1.75% w/w HPC GF, about 20.5% w/wPEG-400, and about 60% w/w isoflurane (204, FIGS. 1A-1B); (e) about 5%w/w propylene glycol, about 10% w/w ethanol, about 10% w/w2-(2-ethoxyethoxy)ethanol, about 6% w/w PEG-3350, about 9% w/w PEG-400and about 60% w/w isoflurane (205, FIGS. 1A-1B); (f) about 23% w/w DMSO,about 15% w/w PPG-400, about 2% w/w HPC GF, and about 60% w/w isoflurane(206, FIGS. 1A-1B); (g) about 2% w/w saccharine, about 78% w/w PEG-300,and about 20% w/w isoflurane (207, FIGS. 1A-1B); (h) about 8% w/wpropylene glycol, about 2% w/w HPC MF, about 20% w/w isopropyl alcohol,and about 70% w/w isoflurane (208, FIGS. 1A-1B); (i) about 38.25% w/wDMSO, about 1.75% w/w HPC GF, and about 60% w/w isoflurane (209, FIGS.1A-1B); (j) about 3% w/w oleic acid, about 15% w/w propylene glycol,about 14.25% w/w ethanol, about 1.75% w/w HPC GF, about 1% w/w poloxamer407, about 5% w/w poloxamer 188, and about 60% w/w isoflurane (210,FIGS. 1A-1B); (k) about 12.5% w/w ethanol, about 20% w/w Gantrez ES-435,about 2.5% w/w propylene carbonate, about 5% w/w 2-(2-ethoxyethoxy)ethanol, and about 60% w/w isoflurane (211, FIGS. 1A-1B); (l) about10.5% w/w ethanol, about 20% w/w Gantrez ES-435, about 2.5% w/wpropylene carbonate, about 5% w/w 2-(2-ethoxyethoxy)ethanol, about 2%w/w HPC MF, and about 60% w/w isoflurane (212, FIGS. 1A-1B); (m) about35% w/w DMSO, about 5% w/w HPC GF, and about 60% w/w isoflurane (213,FIGS. 1A-1B); (n) about 3% w/w oleic acid, about 15.25% w/w propyleneglycol, about 10% w/w ethanol, about 1.75% w/w HPC GF, about 10% w/wPEG-400, and about 60% w/w isoflurane (214, FIGS. 1A-1B); (o) about 15%w/w propylene carbonate, about 10% w/w 2-(2-ethoxyethoxy) ethanol, about15% w/w PEG-400, and about 60% w/w isoflurane (215, FIGS. 1A-1B); (p)about 10% w/w copolymer of PPG-12 and SMDI, about 8.25% w/w ethanol,about 20% w/w Gantrez ES-435, about 1.75% w/w HPC GF, and about 60% w/wisoflurane (216, FIGS. 1A-1B); (q) about 40% w/w DMSO, and about 60% w/wisoflurane (217, FIGS. 1A-1B); (r) about 10% w/w DMSO, about 5% w/w HPCGF, and about 85% w/w isoflurane (218, FIGS. 1A-1B); (s) about 20% w/wDMSO, about 5% w/w HPC GF, and about 75% w/w isoflurane (219, FIGS.1A-1B); (t) about 3% w/w oleic acid, about 14.75% w/w propylene glycol,about 2.25% w/w HPC MF, about 20% w/w PEG-400, and about 60% w/wisoflurane (220, FIGS. 1A-1B); (u) about 3% w/w oleic acid, about 15%w/w propylene glycol, about 2% w/w HPC GF, about 20% w/w PEG-400, andabout 60% w/w isoflurane (221, FIGS. 1A-1B); (v) about 20% w/w GantrezES-435, about 1.75% w/w HPC GF, about 18.25% w/w PEG-400, and about 60%w/w isoflurane (222, FIGS. 1A-1B); (x) about 18% w/w DMSO, about 20% w/wGantrez ES-435, about 2% w/w HPC GF, and about 60% w/w isoflurane (223,FIGS. 1A-1B); (z) about 5% w/w DMSO, about 5% w/w HPC GF, and about 90%w/w isoflurane (224, FIGS. 1A-1B); (y) about 3% w/w oleic acid, about10% w/w copolymer of PPG-12 and SMDI, about 15.25% w/w propylene glycol,about 10% w/w ethanol, about 1.75% w/w HPC GF, and about 60% w/wisoflurane (225, FIGS. 1A-1B); (w) about 37.5% w/w DMSO, about 2.5% w/wHPC MF, and about 60% w/w isoflurane (226, FIGS. 1A-1B); and (aa) about3% w/w oleic acid, about 20.25% w/w propylene glycol, about 15% w/wethanol, about 1.75% w/w HPC GF, and about 60% w/w isoflurane (227,FIGS. 1A-1B).

In certain embodiments, the composition is incorporated in a medicalpatch. In other embodiments, the wound is in the skin of the subject. Inyet other embodiments, the composition is administered locally orregionally. In yet other embodiments, the composition is administered byat least one route from the group selected from intrathecally,epidurally, transdermally, topically, mucosally, buccally, rectally,vaginally, intramuscularly, subcutaneously, by local skin infiltration,and in a nerve block procedure. In yet other embodiments, the paincomprises chronic pain. In yet other embodiments, the compositioncomprises acute pain.

In certain embodiments, the administration of the composition iscontinuous. In other embodiments, the continuous delivery is achieved bya transdermal route or an infusion pump. In yet other embodiments, theadministration of the composition is periodic. In yet other embodiments,the administration of the composition is a one-time event. In yet otherembodiments, the administration of the composition is both periodicallyadministered and continuously administered to the subject on separateoccasions. In yet other embodiments, the pain reduction or prevention isachieved with little or no inhibition of motor function of the subject.In yet other embodiments, the subject is a mammal. In yet otherembodiments, the subject is human, mouse or rat.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIGS. 1A-1B comprise a table illustrating compositions of the inventionuseful for topical application. The table comprises ingredients (% w/w),physical aspect descriptions, and results of in vivo testing using a ratpinprick model.

FIGS. 2A-2B are a series of graphs illustrating mean responses topinprick following 10 minute topical application of selectedformulations of the invention (±SEM). FIG. 2A: Formulation 212 (n=8),FIG. 2B: Formulation 216 (n=9).

FIG. 3 is a graph illustrating a time-dependent evaporation study ofFormulation 212. Control is isoflurane alone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the unexpected discovery that thecompositions of the invention are effective in rapidly reducing orpreventing pain in a subject in need thereof. In one embodiment, thecompositions of the invention are delivering to the subject by a routeother than orally, intravenously, or by inhalation.

The present invention further relates to the unexpected discovery thatthe compositions of the invention penetrate skin quickly, unlike thecurrent topical pain medications, such as topical lidocaine (FIGS.1A-1B). In contrast, unformulated volatile anesthetics quickly penetratehuman skin, but are also quickly lost to the environment.

In one aspect, the compositions of the invention can be formulated sothat the volatility of the volatile anesthetic is reduced (i.e., thevolatile anesthetic evaporates at a reduced rate, and the composition ofthe invention retains its analgesic properties for extended periods oftime) while maintaining its ability of penetrating skin quickly. Inanother aspect, the compositions of the invention have good miscibilitywith pharmaceutically acceptable carriers. In yet another aspect, thecompositions of the invention are more viscous than unformulatedvolatile anesthetics and are thus easier to apply to the skin and do notdisperse from the skin as quickly as unformulated volatile anesthetics.

The present invention overcomes limitations in the prior art byproviding improved anesthetic compositions that are useful in reducingpain in a subject in need of such pain reduction, such as an animalpatient or laboratory animal. In one embodiment, the animal is a mammal.In another embodiment, the mammal is human. In yet another embodiment,the compositions of the invention reduce or prevent pain in a subjectwithout causing a loss of consciousness of the subject. In yet anotherembodiment, the compositions of the invention reduce or prevent pain ina subject without substantially interfering with the motor function ofthe subject.

In one aspect, the compositions of the invention are easily dispensed toa subject, and administration of a composition to the present inventionto the subject can result in a very quick onset of analgesia in thesubject. In another aspect, the compositions of the invention mayquickly dissipate after administration, whereby analgesia may be rapidlyended. In yet another aspect, the compositions of the invention do notcomprise opioid compounds, and this characteristics is advantageous froma practitioner's standpoint, because opioids possess certaindisadvantages, including tolerance, drug interactions, and dependence.

In another aspect, the compositions of the invention are useful fordressing a wound in a subject. In one embodiment, the compositions ofthe invention reduce or prevent pain associated with the wound withoutcausing a loss of consciousness of the subject. In another embodiment,the compositions of the invention reduce or prevent pain associated withthe wound without substantially interfering with the motor function ofthe subject. In yet another embodiment, the compositions of theinvention reduce the time of wound healing or recovery. In yet anotherembodiment, the wound is in the skin of the subject.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in organicchemistry, formulation chemistry and biology are those well-known andcommonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±20% or ±10%, more preferably ±5%,even more preferably ±1%, and still more preferably ±0.1% from thespecified value, as such variations are appropriate to perform thedisclosed methods.

As used herein, the term “topical” as applied to mode of administrationincludes but is not limited to “dermal.” The term “dermal” refers to theapplication of a composition to the skin of a subject. The term “topicalrefers to the application of a composition to the body's naturalsurface, which has not been created by surgical intervention or anyartificial means.

As used herein, the term “wound dressing” refers to an adjunct (such asa chemical and/or material) used by a person for application to a woundto promote healing and/or prevent further harm.

As used herein, the term “to dress a wound” refers to the act ofapplying an adjunct to the wound, in order to improve healing and/orprevent further harm.

As used herein, the terms “inhibiting,” “reducing,” and variations ofthese terms, include any measurable decrease, such as but not limited tocomplete or substantially complete inhibition.

As used herein, the term “preventing” as relating to a condition in asubject refers to the ability of avoiding the onset of the condition ina patient that is likely, susceptible or expected to develop thecondition.

As used herein, the term “effective” means adequate to accomplish adesired, expected, or intended result.

As used herein, the term “or” means “and/or,” unless explicitlyindicated to refer to alternatives only or the alternatives are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

As used herein, the words “comprising” (and any form of comprising, suchas “comprise” and “comprises”), “having” (and any form of having, suchas “have” and “has”), “including” (and any form of including, such as“includes” and “include”) or “containing” (and any form of containing,such as “contains” and “contain”) are inclusive or open-ended and do notexclude additional, unrecited elements or method steps.

As used herein, a “disease” is a state of health of a subject whereinthe subject cannot maintain homeostasis, and wherein if the disease isnot ameliorated then the subject's health continues to deteriorate.

As used herein, a “disorder” in a subject is a state of health in whichthe subject is able to maintain homeostasis, but in which the subject'sstate of health is less favorable than it would be in the absence of thedisorder. Left untreated, a disorder does not necessarily cause afurther decrease in the subject's state of health.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the terms “patient” and “subject” refer to a human or anon-human animals. Non-human mammals include, for example, livestock andpets, such as ovine, bovine, porcine, canine, feline and murine mammals.Preferably, the subject is human.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result can be reduction and/or alleviation ofthe frequency and/or severity of signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Anappropriate therapeutic amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynontoxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutical composition” refers to amixture of at least one compound of the invention with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Multiple techniques of administering a compound exist inthe art including, but not limited to: intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the subject such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the subject. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations. As used herein, “pharmaceuticallyacceptable carrier” also includes any and all coatings, antibacterialand antifungal agents, and absorption delaying agents, and the like thatare compatible with the activity of the compound useful within theinvention, and are physiologically acceptable to the subject.Supplementary active compounds may also be incorporated into thecompositions. The “pharmaceutically acceptable carrier” may furtherinclude a pharmaceutically acceptable salt of the compound useful withinthe invention. Other additional ingredients that may be included in thepharmaceutical compositions used in the practice of the invention areknown in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 20^(th) Ed.,2000, Easton, Pa.), which is incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compounds prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids, organic acids,solvates, hydrates, or clathrates thereof. Suitable pharmaceuticallyacceptable acid addition salts may be prepared from an inorganic acid orfrom an organic acid. Examples of inorganic acids include sulfate,hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric,carbonic, sulfuric, and phosphoric acids (including hydrogen phosphateand dihydrogen phosphate). Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of whichinclude formic, acetic, propionic, succinic, glycolic, gluconic, lactic,malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, 3-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically acceptablebase addition salts of compounds of the invention include, for example,metallic salts including alkali metal, alkaline earth metal andtransition metal salts such as, for example, calcium, magnesium,potassium, sodium and zinc salts. Pharmaceutically acceptable baseaddition salts also include organic salts made from basic amines suchas, for example, N,N′-dibenzylethylene-diamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. All of these salts may be prepared from the correspondingcompound by reacting, for example, the appropriate acid or base with thecompound.

As used herein, the “instructional material” includes a publication, arecording, a diagram, or any other medium of expression that may be usedto communicate the usefulness of the compounds of the invention. In someinstances, the instructional material may be part of a kit useful foreffecting alleviating or treating the various diseases or disordersrecited herein. Optionally, or alternately, the instructional materialmay describe one or more methods of alleviating the diseases ordisorders in a cell or a tissue of a mammal. The instructional materialof the kit may, for example, be affixed to a container that contains thecompounds of the invention or be shipped together with a container thatcontains the compounds. Alternatively, the instructional material may beshipped separately from the container with the intention that therecipient uses the instructional material and the compoundcooperatively. For example, the instructional material is for use of akit; instructions for use of the compound; or instructions for use of aformulation of the compound.

Throughout this disclosure, various aspects of this invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partialnumbers within that range, for example, 1, 2, 3, 4, 5, 5.5 and 6. Thisapplies regardless of the breadth of the range.

Compositions of the Invention

The compositions of the invention are described in a non-limiting mannerherein. The compositions of the invention may be in a liquid, solid orviscous form. In one embodiment, the compositions of the inventions maybe an ointment, a clear solution, a translucent gel, a soft gel, or anycombination thereof. In another embodiment, the compositions of theinvention comprise an emulsion. In yet another embodiment, thecompositions of the invention comprise a liposome or microdroplet.

In one aspect, the compositions of the invention are free of water. Inanother aspect, the compositions of the invention comprise water. In oneembodiment, the compositions of the invention comprise less than 5%water. In another embodiment, the compositions of the invention compriseless than 2.5% water. In yet another embodiment, the compositions of theinvention comprise less than 1% water. In yet another embodiment, thecompositions of the invention comprise less than 0.5% water. In yetanother embodiment, the compositions of the invention comprise less than0.1% water. In yet another embodiment, the compositions of the inventioncomprise less than 0.05% water. In yet another embodiment, thecompositions of the invention are essentially free of water.

In one aspect, the compositions of the invention comprise a halogenatedvolatile compound selected from the group consisting of isoflurane,halothane, enflurane, sevoflurane, desflurane, methoxyflurane, andmixtures thereof. In one embodiment, the halogenated volatile compoundis isoflurane. The compositions of the invention may comprise from about5% to about 95% w/w, about 10% to about 90% w/w, about 20% to about 90%w/w, about 50% to about 90% w/w, about 60% to about 80% w/w, or about60% to about 75% w/w halogenated volatile compound. In one embodiment,the compositions of the invention comprise about 20%, about 50%, about60%, about 70%, about 75%, about 85% or about 90% halogenated volatilecompound. Many of these compounds are racemic mixtures. In oneembodiment, the racemic mixtures are used. In other embodiment, only thed-isomer or the 1-isomer of the compound is used (for examples, see U.S.Pat. Nos. 5,114,715; 5,114,714; and 5,283,372)

In one aspect, the compositions of the invention comprise an alcohol.Non-limiting examples of alcohols contemplated within the inventioninclude methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, t-butanol, or any mixtures thereof. Thecompositions of the invention may comprise from about 1% to about 25%w/w, about 2% to about 20% w/w, about 5% to about 15% w/w, about 5% toabout 10% w/w alcohol. In one embodiment, the compositions of theinvention comprise about 8.25% w/w, about 10% w/w, about 10.5% w/w,about 12.5% w/w, about 14.25% w/w, about 15% w/w, or about 20% w/walcohol.

In one aspect, the compositions of the invention comprise2-(2-ethoxyethoxy)-ethanol. The compositions of the invention maycomprise from about 1% to about 25% w/w, about 2% to about 20% w/w,about 5% to about 15% w/w, about 5% to about 10% w/w2-(2-ethoxyethoxy)ethanol. In one embodiment, the compositions of theinvention comprise from about 2% to about 10% w/w2-(2-ethoxyethoxy)-ethanol. In another embodiment, the compositions ofthe invention comprise about 2.5% w/w, about 5% w/w, or about 10% w/w2-(2-ethoxy ethoxy) ethanol.

In one aspect, the compositions of the invention comprise a polyol.Non-limiting examples of polyols contemplated within the inventioninclude, but are not limited to, ethylene glycol, propylene glycol,glycerol or any mixtures thereof. The compositions of the invention maycomprise from about 5% to about 20.25% w/w polyol. In one embodiment,the compositions of the invention comprise about 5% w/w, about 8% w/w,about 14.75% w/w, about 15% w/w, about 15.25% w/w, or about 20.25% w/wpolyol.

In one aspect, the compositions of the invention comprise an organicsolvent. Non-limiting examples of organic solvents contemplated withinthe invention are dimethylsulfoxide (DMSO), dimethylisosorbide, or anymixtures thereof. The compositions of the invention may comprise fromabout 5% to about 50% w/w organic solvent. In one embodiment, thecompositions of the invention comprise about 5% w/w, about 10% w/w,about 18% w/w, about 20% w/w, about 23% w/w, about 25% w/w, about 28%w/w, about 35% w/w, about 37.5% w/w, about 38.25% w/w, about 40% w/w, orabout 50% w/w DMSO.

In one aspect, the compositions of the invention comprise an organiccarbonate. Non-limiting examples of organic carbonates contemplatedwithin the invention are propylene carbonate and ethylene carbonate. Thecompositions of the invention may comprise from about 2.5% to about 20%w/w organic carbonate. In one embodiment, the compositions of theinvention comprise about 2.5% w/w or about 20% w/w organic carbonate.

In one aspect, the compositions of the invention comprise hydroxypropylcellulose (HPC). HPC (or 2-hydroxypropyl ether of cellulose) is anon-ionic water-soluble ether of cellulose in which some of the hydroxylgroups in the repeating glucose units have been hydroxypropylatedforming —OCH₂CH(OH)CH₃ groups using propylene oxide. The average numberof substituted hydroxyl groups per glucose unit is referred to as thedegree of substitution (DS), with complete substitution providing a DSof 3. Because the hydroxypropyl group added contains a hydroxyl group,this can also be etherified during preparation of HPC. When this occurs,the number of moles of hydroxypropyl groups per glucose ring, moles ofsubstitution (MS), can be higher than 3. Non-limiting examples ofcommercially available HPC are HPC GF, HPC MF, or any mixtures thereof.HPC GF has a solution viscosity of 150-400 mPas in water (2% perweight), and 75-400 mPas in ethanol (2% per weight). HPC MF has asolution viscosity of 4,000-6,500 mPas in water (2% per weight), and3,000-6,500 mPas in ethanol (2% per weight). The compositions of theinvention may comprise from about 1% to about 5% w/w HPC. In oneembodiment, the compositions of the invention comprise about 1.75% w/w,about 2% w/w, about 2.25% w/w, about 2.5% w/w, or about 5% w/w HPC.

In one aspect, the compositions of the invention comprise a fatty acidor a salt thereof. Non-limiting examples of fatty acids contemplatedwithin the invention are myristoleic acid, palmitoleic acid, sapienicacid, oleic acid, elaidic acid, vaccenic acid, linoleic acid,linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoicacid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, cerotic acid, or any mixtures thereof.The compositions of the invention may comprise from about 1% to about 5%w/w fatty acid or a salt thereof. In one embodiment, the compositions ofthe invention comprise about 3% w/w fatty acid or a salt thereof.

In one aspect, the compositions of the invention may comprise apolyethylene glycol (PEG). Non-limiting examples of PEGs contemplatedwithin the invention are PEG-200, PEG-300, PEG-400, PEG-600,PEG-[950-1,050], PEG-1,000, PEG-[1,300-1,600], PEG-[1,305-1,595],PEG-1,450, PEG-1,500, PEG-2,000, PEG-2,050, PEG-3,000,PEG-[3,000-3,700], PEG-3,350, PEG-4,000, PEG-4,600, PEG-6,000,PEG-8,000, PEG-10,000, PEG-12,000, PEG-20,000, PEG-35,000, or anymixtures thereof, wherein the number associated with the PEG indicatesthe approximate average molecular weight of the oligomer or polymer. Thecompositions of the invention may comprise from about 5% to about 80%w/w PEG, or from about 6% to about 78% w/w PEG. In one embodiment, thecompositions of the invention comprise about 6% w/w, about 9% w/w, about10% w/w, about 15% w/w, about 18.25% w/w, about 20% w/w, about 20.5% orabout 78% w/w PEG.

In one aspect, the compositions of the invention may comprise apolypropylene glycol (PPG). Non-limiting examples of PEGs contemplatedwithin the invention are PPG-400, PPG-1000, PPG-1650, PPG-2250, andPPG-4000, or any mixtures thereof, wherein the number associated withthe PPG indicates the approximate average molecular weight of theoligomer or polymer. The compositions of the invention may comprise fromabout 15% to about 20% w/w PPG, or about 15% w/w PPG.

In one aspect, the compositions of the invention may comprise amonoalkyl ester of a (methyl vinyl ether-maleic acid) co-polymer. In oneembodiment, the ester is n-butyl (such as GANTREZ A-425®, GANTREZES-425®, or GANTREZ ES-435®), isopropyl (such as GANTREZ ES-335®), orethyl (such as GANTREZ SP-215® or GANTREZ ES-225®). The compositions ofthe invention may comprise from about 15% to about 25% w/w monoester ofa (methyl vinyl ether-maleic acid) co-polymer. In one embodiment, thecompositions of the invention comprise about 20% w/w monoester of a(methyl vinyl ether-maleic acid) co-polymer.

In one aspect, the compositions of the invention may comprise acopolymer of PPG-12 (also known as 2-(2-hydroxypropoxy)propan-1-ol) andSMDI (also known as 1,1-methylenebis4-isocyanatocyclohexane or methylenebis(4-cyclohexylisocyanate) polymer. In one embodiment, the compositionsof the invention comprise about 5% w/w to about 15% w/w copolymer ofPPG-12 and SMDI. In another embodiment, the compositions of theinvention comprise about 10% w/w copolymer of PPG-12 and SMDI.

In one aspect, the compositions of the invention may comprise apoloxamer. Poloxamers are nonionic triblock copolymers composed of acentral hydrophobic chain of polyoxypropylene (poly(propylene oxide))flanked by two hydrophilic chains of polyoxyethylene (poly(ethyleneoxide)). Poloxamers are also known by the trade names Synperonics,Pluronics and Kolliphor. For the generic term “poloxamer”, thesecopolymers are commonly named with the letter “P” (for poloxamer)followed by three digits, the first two digits×100 give the approximatemolecular mass of the polyoxypropylene core, and the last digit×10 givesthe percentage polyoxyethylene content (e.g., P407=poloxamer with apolyoxypropylene molecular mass of 4,000 g/mol and a 70% polyoxyethylenecontent; P188=poloxamer with a polyoxypropylene molecular mass of 1,800g/mol and a 80% polyoxyethylene content). For the Pluronic trade name,coding of these copolymers starts with a letter to define its physicalform at room temperature (L=liquid, P=paste, F=flake (solid)) followedby two or three digits. The first digit (two digits in a three-digitnumber) in the numerical designation, multiplied by 300, indicates theapproximate molecular weight of the hydrophobe; and the last digit×10gives the percentage polyoxyethylene content (e.g., L61=Pluronic with apolyoxypropylene molecular mass of 1,800 g/mol and a 10% polyoxyethylenecontent). In the example given, poloxamer 181 (P181)=Pluronic L61,poloxamer 407=Pluronic F127. In one embodiment, the compositions of theinvention comprise from about 1% to about 5% w/w poloxamer, or about 1%w/w poloxamer, or about 5% w/w poloxamer. In another embodiment, thepoloxamer comprises poloxamer 188 or poloxamer 407.

In one aspect, the compositions of the invention comprise saccharine. Inone embodiment, the compositions of the invention comprise about 2% w/wsaccharine.

Various concentrations of each component contemplated within theinvention may be used to generate the composition of the invention. Forexample, a composition of the invention comprising a component maycomprise about 0.1%-99%, 0.1%-60%, 5%-50%, 10%-40%, 5%-25%, 10%-30%,10%-25%, 25%-50%, 10%-75%, 25%-75%, 10%-65%, 25%-65%, 10%-60%, 25%-60%,0.1%, 1%, 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80% or any range derivable therein, of the component.

In one aspect, the compositions of the invention further include atleast one local anesthetic, such as but not limited to lidocaine,tetracaine, benzocaine, and prilocaine. In one embodiment, the at leastone anesthetic is physically separated from the halogenated volatilecompound. In another embodiment, the at least one anesthetic is inphysical contact with the halogenated volatile compound.

The components of the compositions of the invention may be combinedusing methods known to those skilled in the art. Non-limiting proceduresfor preparing the compositions of the invention are provided in theExamples section.

The delivery of the volatile anesthetic composition may be continuous,periodic, a one-time event, or the volatile anesthetic composition maybe both periodically administered and continuously administered to thesubject on separate occasions.

At least one component of the compositions of the invention may providesubstantial advantages, including improving the physicalcharacteristics, pharmacological properties, and/or the ease of use ofthe halogenated volatile compound, wherein the at least one component isselected from the group consisting of an alcohol, an organic solvent, anorganic carbonate, hydroxypropyl cellulose (HPC), a fatty acid or a saltthereof, a polyethylene glycol (PEG), a monoester of a (methyl vinylether-maleic acid) co-polymer, and any mixtures thereof. The at leastone component may interact with the halogenated volatile compound in anon-azeotropic fashion to effectively reduce vaporization or evaporationof the halogenated volatile compound. In this way, the shelf-life,durability, skin penetrability, and/or ease of use of the halogenatedvolatile compound composition are improved. The at least one componentmay also improve the ease of mixing the composition prior toadministration. Additionally, the pharmacokinetics of the halogenatedvolatile compound may be altered by the presence of the at least onecomponent to provide improved pain relief. For example, without wishingto be bound by any theory, the at least one component may maintain thehalogenated volatile compound in a particular region more effectivelyand/or help deliver the halogenated volatile compound to the site(s) ofaction.

The component may also increase the viscosity of the halogenatedvolatile compound. Increased viscosity of the halogenated volatilecompound may also improve the ease of handling and applying thecompositions of the invention.

The invention further contemplates using the compositions of theinvention in medical patches. In one embodiment, the composition of theinvention is incorporated in a medical patch, which is made of materialsthat are compatible with the composition of the invention. Preparationand use of a medical patch is known to those skilled in the art. Thepatch comprising the composition of the invention may be applied to theskin of the subject, providing localized analgesic relief thereof. Inone embodiment, a composition of the invention may comprise from about10% to about 100% w/w, about 20% to about 95% w/w, about 50% to about90% w/w, about 60% to about 80% w/w, or about 60% to about 75% w/whalogenated volatile compound. In one embodiment, a composition of theinvention comprises about 20%, about 50%, about 60%, about 70%, about75%, about 85% or about 100% halogenated volatile compound.

The present invention also contemplates a sealed container comprisingthe composition of the present invention. The interior of the containermay be sterile. The container may comprise a stopper which can be easilypierced by an injection needle. The container may comprise the chamberportion of a syringe. The container may comprise a drip chamber. Thedrip chamber may be coupled to a catheter. The catheter may be anepidural catheter or an intrathecal catheter. The container can be asyringe, a tube, a plastic bag, a collapsible plastic bag, a glassbottle, a glass ampoule, or a plastic bottle. The container may becoupled to an infusion pump. The infusion pump may be an intrathecalpump, an epidural delivery infusion pump, or a patient control analgesia(PCA) pump. The infusion pump may be programmable.

The halogenated volatile compound may be dissolved into the solution inany number of ways, such as the procedure illustrated in Example 1. Inother non-limiting examples, it may be bubbled through the solution, forexample, using a vaporizer, or it may be solubilized by agitation or bysonication. In one embodiment, a halogenated volatile compound may bemeasured in liquid form and directly mixed into a solution. Of course,other suitable methods of dissolving the halogenated volatile compoundinto solution may also be used. After the halogenated volatile compoundhas been formulated, it may be administered to a subject in need of painreduction.

In one aspect, pharmaceutical compositions of the present inventioncomprise an effective amount of one or more halogenated volatilecompound dissolved or dispersed in a pharmaceutically acceptablecarrier. The preparation of a pharmaceutical composition that containsat least one halogenated volatile compound will be known to those ofskill in the art in light of the present disclosure, as exemplified byRemington, The Science and Practice of Pharmacy (20^(th) Ed., 2000),which is incorporated herein by reference in its entirety. Moreover, foranimal (for example, human) administration, it will be understood thatpreparations should meet sterility, pyrogenicity, and general safety andpurity standards as required by FDA Office of Biological Standards.

In one embodiment, the compositions of the present invention furthercomprise cyclodextrin. Cyclodextrins are a general class of moleculescomposed of glucose units connected to form a series of oligosaccariderings (Challa et al., 2005, AAPS PharmSciTech 6:E329-E357). In nature,the enzymatic digestion of starch by cyclodextrin glycosyltransferase(CGTase) produces a mixture of cyclodextrins comprised of 6, 7 and 8anhydroglucose units in the ring structure (α-, β-, and γ-cyclodextrin,respectively). Commercially, cyclodextrins are also produced fromstarch, but different, more specific enzymes are used. Cyclodextrinshave been employed in formulations to facilitate the delivery ofcisapride, chloramphenicol, dexamethasone, dextromethoraphan,diphenhydramine, hydrocortisone, itraconazole, and nitroglycerin(Welliver & McDonough, 2007, Sci World J, 7:364-371). In one embodiment,the cyclodextrin of the invention is hydroxypropyl-Beta-cyclodextrin,sulfobutylether-beta-cyclodextrin, alpha-dextrin or combinationsthereof. In another embodiment, cyclodextrin is used as a solubilizingagent.

In one embodiment, a preservative or stabilizer may be included in thecomposition or solution. For example, the prevention of the action ofmicroorganisms may be brought about by preservatives such as variousantibacterial and antifungal agents, including but not limited toparabens (for example, methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, EDTA, metabisulfite, benzyl alcohol, thimerosal orcombinations thereof. Agents that may be included suitable forinjectable use include sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions (U.S. Pat. No. 5,466,468, specificallyincorporated herein by reference in its entirety). The compositions arepreferably sterile and should be fluid in case of injection. Solutionsare preferably stable under the conditions of manufacture and storageand must be preserved against the contaminating action ofmicroorganisms, such as bacteria and fungi. Non-limiting examples ofstabilizers which may be included include buffers, amino acids such asglycine and lysine, carbohydrates such as dextrose, mannose, galactose,fructose, lactose, sucrose, maltose, sorbitol, and mannitol. Appropriatestabilizers or preservatives may be selected according to the route ofadministration desired. A particle filter or microbe filter can be used,and may be necessary according to the route of administration desired.

The composition may be sterilized prior to administration. Methods forsterilization are well known in the art and include heating, boiling,pressurizing, filtering, exposure to a sanitizing chemical (for example,chlorination followed by dechlorination, UV radiation exposure orremoval of chlorine from solution), aeration, autoclaving, and the like.

Emulsions

As would be understood by one of skill, an emulsion consists of amixture of two or more immiscible liquids (i.e., contains multiplephases). Emulsions are thus distinct from solutions, which contain oneor essentially only one phase. One of the liquids (the dispersed phase)is dispersed in the other (the continuous phase). In one type ofemulsion, a continuous liquid phase surrounds droplets of water (forexample, a water-in-oil emulsion). In another type of emulsion, oil isdispersed within a continuous water phase (for example, an oil-in-wateremulsion). Similarly, emulsification is the process by which emulsionsare prepared.

In one embodiment, the compositions of the invention comprise anemulsion, such as a water-in-oil or an oil-in-water emulsion, including,but not limited to a lipid emulsion, such as a soybean oil emulsion. Forexample, the compositions of the invention comprise a lipid emulsion oran oil-in-water emulsion. Lipid compositions, lipid emulsions,water-in-oil emulsions, and/or oil-in-water emulsions may be useful forthe intrathecal, epidural, transdermal, topical, mucosal, buccal,rectal, vaginal, intramuscular, or subcutaneous delivery of thecompositions of the invention. Certain emulsions of isoflurane have beenprepared previously for intravenous (da Silva Telles et al., 2004, Rev.Bras. Anaestesiol Campianas 54(5):2004) or epidural administration (Chaiet al., 2008, Br. J. Anesth. 100:109-115; Chai et al., 2006, Anesth.105:A743), both for inducing anesthesia.

The emulsion of the invention may further comprise an emulsifier.Emulsions of the invention may also include, but are not limited to,nanoemulsions, which are emulsions with a mean droplet size less thanthose of emulsions. Nanoemulsions are sometimes referred to asmicroemulsions and submicroemulsions. Often, the physical appearance ofa nanoemulsion is transparent, rather than the often milky appearance ofan emulsion, due to the reduced mean droplet size.

In one embodiment, the emulsion of the invention has a lipid component.In another embodiment, the lipid component comprises an amount rangingfrom about 1% to 99%, from about 5% to about 75%, from about 10% toabout 60%, from about 20% to about 50%, or from about 30% to about 40%,w/w of the emulsion. In yet another embodiment, the lipid component ofthe emulsion is soybean oil, long chain triglyceride, castor oil, cornoil, cottonseed oil, olive oil, peanut oil, peppermint oil, saffloweroil, sesame oil, soybean oil, hydrogenated soybean oil, hydrogenatedvegetable oil, medium chain triglycerides coconut oil, palm seed oil andderivatives, medium chain (C8/C10) mono- and diglycerides,d-alpha-tocopherol, soy fatty acids, or combinations thereof. In yetanother embodiment, the lipid component of the emulsion is soybean oil.Commercially available lipid compositions that may be useful for theproduction of the volatile anesthetic compositions of the presentinvention include, but are not limited to, INTRALIPID®, LIPOSYN®, andNUTRILIPID®.

In one embodiment, the emulsion further comprises an emulsifier oremulgent. An emulsifier may also be a surfactant. In one embodiment, theemulsifier ise egg phospholipid, purified egg phospholipids, Polyoxyl 35castor oil (Cremophor EL), Polyoxyl 40 hydrogenated castor oil(Cremophor RH 40), Polyoxyl 60 hydrogenated castor oil (Cremophor RH60), Polysorbate 20, Polysorbate 80, d-alpha-tocopheryl polyethyleneglycol 1000 succinate, Solutol HS-15, propylene glycol or combinationsthereof. Various concentrations of an emulsifier may be used with thepresent invention. For example, the compositions of the presentinvention may comprise about 0.1%-99%, 0.1%-60%, 5%-50%, 10%-40%,5%-25%, 10%-30%, 10%-25%, 25%-50%, 10%-75%, 25%-75%, 10%-65%, 25%-65%,10%-60%, 25%-60%, 0.1%, 1%, 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80% or any range derivable therein, of anemulsifier.

In one embodiment, the emulsion of the invention has a perfluorocarboncomponent. In another embodiment, the perfluorocarbon componentcomprises an amount ranging from about 0.1% to 99%, from about 5% toabout 75%, from about 10% to about 60%, from about 20% to about 50%, orfrom about 30% to about 40%, w/w of the emulsion. In yet anotherembodiment, perfluorocarbon is advantageous due to its limited toxicityand ability to scavenge a large amount of gas.

Liposomes and Microdroplets

In one embodiment, the compositions of the invention are encapsulated,micro-encapsulated or nano-encapsulated. In one embodiment, thecompositions of the invention comprise a liposome suspension.

A liposome (for example, multilamellar, unilamellar, and/ormultivesicular liposomes) is a microscopic, spherical, fluid-filledstructure, with walls comprising one or more layers of phospholipids andmolecules similar in physical and/or chemical properties to those thatmake up mammalian cell membranes. By way of non-limiting examples,liposomes may be formed from a variety of natural membrane components,such as cholesterol, stearylamine, or phosphatidylcholine (for example,U.S. Pat. Nos. 5,120,561 and 6,007,838, each of which is incorporatedherein by reference in its entirety), or of pure surfactant componentslike DOPE (dioleoylphosphatidylethanolamine). Liposomes may beformulated to incorporate a wide range of materials as a payload eitherin the aqueous or in the lipid compartments or in both. Generally,lipophilic active substances dissolve in the bilayer, amphiphilicsubstances become associated with the phospholipid membrane andhydrophilic substances occur in solution in the enclosed aqueous volume(Artmann et al., 1990, Drug Res. 40 (II) Nr. 12 pp. 1363-1365;incorporated herein by reference in its entirety).

Liposomes useful as drug carriers or for topical use are non-toxic andavailable in industry (Gehring et al., 1990, Drug Res. 40 (II) Nr. 12,pp. 1368-1371; incorporated herein by reference in its entirety).Liposomes have been used as carriers for lipophilic drugs like theanti-tumor and the anti-viral derivatives of azidothymidine (AZT)(Kamps, et al., 1996, Biochim. Biophys. Acta 1278:183-190). Insulin hasalso been delivered via liposomes (Muramatsu et al., 1999, Drug Dev.Ind. Pharm. 25:1099-1105). For medical uses as drug carriers, theliposomes may be injected, and when they are modified with lipids, theirsurfaces become more hydrophilic and hence their ability to persist canbe increased. Polyethylene glycol-modified liposomes have been used ascarriers for hydrophilic (water-soluble) anti-cancer drugs likedoxorubicin. Liposomal derivatives of mitoxantrone and others areespecially effective in treating diseases that affect the phagocytes ofthe immune system because they tend to accumulate in the phagocytes,which recognize them as foreign invaders (Rentsch et al., 1997, Br. J.Cancer 75:986-992). The versatility of liposomes, due to the variablecomposition, enables liposomes to be used to deliver vaccines, proteins,nucleotides, plasmids, drugs, cosmetics, or the volatile anesthetics ofthe invention to the body.

Liposome compositions of the invention can comprise any range ofliposome and other components, according to the methods and detaileddescription set forth herein. By way of a non-limiting example, aliposome component of a composition of the invention may include from0.1% to 99.9% liposome component, or more preferably, from 0.1%-50%liposome component, and even more preferably, from 0.1%-30% liposomecomponent. In one embodiment, the liposome of the invention comprisescholesterol, stearylamine, phosphatidylcholine,dioleoylphosphatidylethanolamine, or combinations thereof.

In one embodiment, the compositions of the invention comprise amicrodroplet. A microdroplet of the invention consists of a sphere oforganic liquid phase drug that ranges in diameter from about 200Angstroms to about 10,000 Angstroms that is covered by a monolayer of asuitable lipid. Preferred lipids are phospholipids, which are naturalconstituents of biological membranes and as such are biologicallycompatible. Compounds useful for preparing microdroplets includephosphatidylcholine (lecithin), sphingomyelin, phosphatidic acid,phosphatidyl serine, phosphatidyl inositol, diphosphatidyl glycerol andphosphatidyl glycerol.

Microdroplets may be prepared by sonication, including probe or bathsonication, homogenization, microfluidization or by high intensitymechanical agitation. The preferred method of preparing themicrodroplets of the invention is by sonication with a probe sonicator.Alternatively, microdroplets may be prepared in a bath sonicator. Forsmall scale preparations a 1.0 cm diameter test tube is suspended, withuse of a test-tube clamp, in a bath sonicator filled with water. Thecomponents of the microdroplet are first grossly mixed by shaking,Vortex mixing, Polytron or other methods. The suspension is thenintroduced into the bath sonicator and sonicated for 1-2 hours. If thepreparation is to be done on a large scale, it is possible to omit thetest tube and introduce the components of the microdroplet directly intoa bath sonicator. Microdroplets may also be produced by high intensitymechanical agitation. Useful methods include a Waring blender, aPolytron and high frequency shakers such as a commercial paint shaker.Other materials and methods useful in the preparation of microdropletsare known in the art and are described in U.S. Pat. Nos. 4,622,219,4,725,442, 5,091,188, Haynes et al. (1989, J Controlled Release 9:1-12)and Haynes et al. (1985, Anesthesiology 63:490-499), all of whichreferences are incorporated herein in their entirety.

Methods

The invention includes a method of treating or preventing pain in asubject in need thereof. The method comprises administering to thesubject a therapeutically effective amount of a composition of theinvention, whereby the pain in the subject is treated or prevented. Theinvention further includes a method of dressing a wound in a subject.

In one aspect, the compositions of the invention are administered to thesubject by a route other than orally, intravenously, or by inhalation.Preferably, the administration comprises local or regional delivery,such as, for example, transdermal, topical, mucosal, buccal, rectal,vaginal, intramuscular, subcutaneous, intrathecal or epidural delivery,of a composition of the invention to the subject in an amount effectiveto reduce chronic or acute pain. In one embodiment, the composition ofthe invention is administered dermally in an amount sufficient to reduceor prevent pain. As used herein, the phrase “pain reduction” is intendedto cover pain reduction as a result of anesthesia, analgesia, and/or theinhibition of neural impulses involved in pain perception, e.g., viapartial nerve conduction block. In one embodiment, the composition ofthe invention is delivered to a portion of the subject in an amount andin a manner effective to reduce pain. In another embodiment, thecomposition of the invention is delivered to a portion of the subject inan amount and in a manner effective to reduce pain without substantiallyinterfering with motor function of the subject. In yet anotherembodiment, the compositions of the invention reduce the time of woundhealing or recovery. In yet another embodiment, the wound is in the skinof the subject.

The delivery of the composition may be continuous, periodic, a one-timeevent, or the composition may be both periodically administered andcontinuously administered to the subject on separate occasions. If theadministration is intrathecal or epidural, the composition may be freeor essentially free of a lipid emulsion. The composition may bedelivered intrathecally, epidurally, or in a nerve block procedure, torelieve, for example, chronic pain or acute pain. In one embodiment, thecomposition is administered locally or topically prior to a proceduresuch as a venipuncture, an injection (e.g., BOTOX™), a peripheral venouscannulation, incision, hair removal, tattoo application and removal,mammography, or other procedure. In another embodiment, the volatileanesthetic composition is administered via non-topical routes.

Combination Therapies

In one aspect, the compositions of the invention comprise a halogenatedvolatile compound and at least one anesthetic and/or analgesic. The atleast one anesthetic and/or analgesic may comprise a commerciallyavailable compound that is known to provide anesthesia to a subject. Inone embodiment, the anesthetic and/or analgesic is at least one selectedfrom group consisting of lidocaine, tetracaine, benzocaine, prilocaine,a non-steroidal anti-inflammatory drug (such as but not limited toibuprofen and diclofenac), another analgesics suitable for topicaldelivery (such as, but not limited to, acetaminophen and ketamine), asalt thereof and mixtures thereof.

In one embodiment, the at least one anesthetic and/or analgesic isphysically separated from the halogenated volatile compound. In anotherembodiment, the at least one anesthetic and/or analgesic is in physicalcontact with the halogenated volatile compound. In yet anotherembodiment, the at least one anesthetic and/or analgesic is incorporatedin a medical patch. In yet another embodiment, the halogenated volatilecompound is incorporated in a medical patch. In yet another embodiment,the at least one anesthetic and/or analgesic and halogenated volatilecompound are incorporated in a medical patch.

In one non-limiting embodiment, once the composition comprising ahalogenated volatile compound and at least one anesthetic and/oranalgesic is administered to the subject, the halogenated volatilecompound provides analgesia within a short period of time from theadministration, and the at least one anesthetic and/or analgesicprovides analgesia within a longer period of time from theadministration. In another non-limiting embodiment, the compositioncomprising the halogenated volatile compound and the at least oneanesthetic and/or analgesic provides substantially continuous painrelief to the subject. In yet another non-limiting embodiment, thehalogenated volatile compound and the at least one anesthetic and/oranalgesic act synergistically in reducing or preventing pain in thesubject.

A synergistic effect between the halogenated volatile compound and atleast one anesthetic may be calculated, for example, using suitablemethods such as, for example, the Sigmoid-E_(max) equation (Holford &Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loeweadditivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.Enzyme Regul. 22: 27-55). Each equation referred to above may be appliedto experimental data to generate a corresponding graph to aid inassessing the effects of the drug combination. The corresponding graphsassociated with the equations referred to above are theconcentration-effect curve, isobologram curve and combination indexcurve, respectively.

Dosing

The amount of the composition of the invention to be administered, forexample, dermally, depends on the particular indication desired. Forexample, the dose depends on the type of pain intended to be treated.The dose may be different, for instance, if the delivery of thecomposition is intended to reduce chronic pain as opposed to acute pain.The subject's physical characteristics may also be important indetermining the appropriate dosage. Characteristics such as weight, age,and the like may be important factors. For example, the composition mayhave increased potency with age.

The particular dosage may also be dependent on the dosing regime chosen.For example, the composition may be delivered continuously orperiodically. Conversely, the composition may be administered as asingle administration as a one-time event.

The concentration of the halogenated volatile compound in solution mayvary. For example, a solution may contain a halogenated volatilecompound in a w/w ratio of from about 5 to about 95%, from about 10 toabout 90%, from about 20 to about 90%, from 50 to about 90%, from about60 to about 80%, from about 60 to about 75%, from about 20 to about 80%,from about 25 to about 75%, from about 30 to about 70%, from about 40 toabout 60%, from about 1 to about 15%, from about 1 to about 10%, fromabout 1 to about 5%, or any range derivable therein.

The dosing and manner of delivery of the compositions of the inventionmay be adjusted to achieve pain prevention or reduction withoutsubstantially interfering with motor function of the subject, forexample, by varying the amount, concentration, frequency ofadministration, and timing of administration.

The compositions of the invention may also contain one or moreadditives, such as a surfactant, PVP, a polymer, an antimicrobial agent,a preservative etc. In one embodiment, a composition of the presentinvention comprises about 0.1-90% of a halogenated volatile compoundsuch as isoflurane, methoxyflurane, or sevofluorane, 0.1-99% of asolvent such as NMP or DMSO, and 0-50% other additive(s) (for example,glycerol, a surfactant, or PVP). In one embodiment, it may be desirableto produce a concentrated formulation which may be subject to a finaldilution prior to administration.

Compositions of the invention may be administered regionally or locallyby a route other than orally, intravenously or by inhalation. “Regional”or “local” administration allow for the preferential delivery of acomposition of the invention to a specific region of the body, such asnear a nerve or a nerve bundle. In contrast, systemic/generaladministration allows for the systemic administration of a volatileanesthetic, for example, via intravenous administration. Regional orlocal administration typically allows for a lower total bodyconcentration (although elevated local concentrations) of a compositionto be administered to a subject for analgesia or diminished painperception of at least a portion of the subject's body. In oneembodiment, the compositions of the invention include from about 100 toabout 750,000 ng/mg, from about 100 to about 250,000 ng/mg, from about100 to about 100,000 ng/mg, from about 100 to about 50,000 ng/mg, fromabout 100 to about 25,000 ng/mg, or from about 100 to about 10,000 ng/mgof the halogenated volatile compound. The specific concentration ofhalogenated volatile compound used may vary depending on the desiredeffect, and in various embodiments the volatile anesthetic compositionis titrated for effect: thus the concentration of halogenated volatilecompound used or achieved in tissues may vary depending on the specificdesired result and/or the particular characteristics of the patient suchas sensitivity to the halogenated volatile compound.

The present invention may be used with various nerve block procedures.Nerve block procedures according to the present invention may beperformed with or without ultrasound visualization; for example, anultrasound machine may be used to visualize the region of the bodyinvolved in the nerve block procedure, such as, for example, variousnerve bundles in the shoulder, neck, lower back, etc. The inventorsenvision that the present invention may be used in conjunction with avariety of surgical procedures, including, for example, but not limitedto, knee replacement, hip replacement, shoulder replacement, and/orbirthing-related procedures.

In one embodiment, compositions and methods of the present invention maybe used for pain management. Pain management is distinct from generalanesthesia in that a lower total body concentration of a halogenatedvolatile compound may be administered to a subject to increase analgesiaor decrease perception of pain, preferably without rendering the subjectunconscious or substantially interfering with motor function. In oneembodiment, specific concentrations of a halogenated volatile compoundused for pain management include from about 100 to about 750,000 ng/mg,from about 100 to about 250,000 ng/mg, from about 100 to about 100,000ng/mg, from about 100 to about 50,000 ng/mg, from about 100 to about25,000 ng/mg, or from about 100 to about 10,000 ng/mg of the halogenatedvolatile compound.

Local topical administration to achieve analgesia prior to or during amedical procedure may be accomplished using techniques known in the art.Examples of such medical procedures include, but are not limited to,surgery, venipuncture, injection, peripheral venous cannulation,incision, suturing, or other procedure.

Other routes of administration contemplated include injection, infusion,continuous infusion, localized perfusion bathing target cells directly,via a catheter, via nanoparticle delivery, topical administration (forexample, in a carrier vehicle, a topical control release patch, in awound dressing, a hydrocolloid, a foam, or a hydrogel), intra-articular,intracranial, and/or intratumoral. An appropriate biological carrier orpharmaceutically acceptable excipient may be used. Compoundsadministered may, in various embodiments, be racemic, isomericallypurified, or isomerically pure.

In one embodiment, the compositions of the invention are notadministered intravenously. Intravenous administration typically resultsin the rapid distribution of the composition throughout the body of asubject. Thus, in certain embodiments, intravenous administration isincompatible for use with regional or local analgesia.

Those skilled in the art recognize, or are to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures, embodiments, claims, and examples described herein. Suchequivalents were considered to be within the scope of this invention andcovered by the claims appended hereto. For example, it should beunderstood, that modifications in reaction conditions, including but notlimited to reaction times, reaction size/volume, and experimentalreagents, such as solvents, catalysts, pressures, atmosphericconditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents,with art-recognized alternatives and using no more than routineexperimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

Other objects, features and advantages of the present invention willbecome apparent from the detailed description herein. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

EXAMPLES

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless otherwise specified. Thus, the invention should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

Example 1: Formulation Manufacturing Method

All excipients except for viscosity enhancer(s)/gelling agents (i.e.,hydroxypropyl cellulose GF or hydroxypropyl cellulose MF) were measuredinto a vessel that can be sealed to prevent loss of any volatilecompounds present in the formulation (active or excipient). The vesselwas made of material compatible for use with isoflurane and the variousexcipients (e.g., glass). The vessel was sealed at all times except whenadding excipients or active. This mixture was then stirred using anappropriate method for the batch size (e.g., magnetic stir bar, mixer)to completely mix all the added excipients.

Isoflurane was then added with a 5% overage to account for any lossduring compounding or sample transfer. After addition of the active, theformulation was stirred until uniform.

For those formulations wherein a viscosity enhancer/gelling agent waspresent, the agent was slowly added and mixed until all agent wascompletely incorporated. If the formulation viscosity became too high tomix using the stirring method (i.e., magnetic stir bar) an additionalmixing using an appropriate method was performed. The formulation wasstored overnight to complete solvation. On the next day, one finalmixing was performed prior to use or transfer to another container forstorage.

Example 2: In Vivo Testing Method Using Pinprick

The analgesic effect of topically applied formulations on the skin wasassessed in an in vivo rat model using a pinprick test.

Twenty four hours prior to testing, the dorsal thoracolumbar area ofeach rat was shaved. On the testing day, formulation was applied to afoil-backed gauze pad (2 cm×2 cm). Pads were applied (gauze side down)to the shaved thoracolumbar region, sealed with occlusive adhesive wrapand maintained for the five or ten minute application period. Followingthe desired application time, the pad was removed and any remaining drugwiped away.

Analgesia was then assessed at intervals by performing a series of sixpinpricks with a von Frey instrument. As a control, an untreated areawas also tested in the same manner. Rats normally responded to pinprickwith a muscle reflex, vocalization or avoidance. Inhibition of suchresponse was assessed following drug treatment.

Example 3: Evaporation Studies

A time-dependent evaporation study was performed with a composition ofthe invention (FIG. 3). Isoflurane alone was used as the control in theexperiment. As illustrated in FIG. 3, the volatility of the volatileanesthetic in the composition of the invention was reduced as comparedto the neat volatile anesthetic. After 45 minutes of experiment, 95.06%of original weight of Formulation 212 remained (i.e., 4.94% of thecomposition was lost due to evaporation), while only 86.8% of neatisoflurane remained (i.e., 13.2% of isoflurane was lost to evaporation).

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1-56. (canceled)
 57. A method of reducing or ameliorating pain in asubject, the method comprising administering to the subject atherapeutically effective amount of a uniform composition comprising ahalogenated volatile compound and hydroxypropyl cellulose (HPC); whereinthe halogenated volatile compound is selected from the group consistingof isoflurane, halothane, enflurane, sevoflurane, desflurane,methoxyflurane, and any mixtures thereof.
 58. The method of claim 57,wherein the composition comprises about 5% to about 95% w/w halogenatedvolatile compound.
 59. The method of claim 57, wherein the compositioncomprises about 50% to about 90% w/w halogenated volatile compound. 60.The method of claim 57, wherein the composition further comprises atleast one selected from the group consisting of an alcohol; a polyol; anorganic solvent; an organic carbonate; a fatty acid or a salt thereof; apolyethylene glycol (PEG); a polypropylene glycol (PPG); a copolymer of2-(2-hydroxypropoxy)propan-1-ol (PPG-12) and 1-methylenebis-4-isocyanatocyclohexane (SMDI); a poloxamer; saccharine;2-(2-ethoxyethoxy)-ethanol; a monoester of a (methyl vinyl ether-maleicacid) co-polymer; and any combinations thereof; wherein the polyol isselected from the group consisting of ethylene glycol, propylene glycol,glycerol, and any mixtures thereof, wherein the organic solvent isselected from the group consisting of dimethylsulfoxide (DMSO),dimethylisosorbide, and any mixtures thereof, and wherein the organiccarbonate is selected from the group consisting of propylene carbonate,ethylene carbonate and any mixtures thereof.
 61. The method of claim 60,wherein at least one applies: the alcohol is selected from the groupconsisting of methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, t-butanol, and any mixtures thereof; the fattyacid or salt thereof is selected from the group consisting ofmyristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidicacid, vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid,arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoicacid, caprylic acid, capric acid, lauric acid, myristic acid, palmiticacid, stearic acid, arachidic acid, behenic acid, lignoceric acid,cerotic acid, and any combinations thereof the PEG is selected from thegroup consisting of PEG-200, PEG-300, PEG-400, PEG-600, PEG-[950-1,050],PEG-1,000, PEG-[1,300-1,600], PEG-[1,305-1,595], PEG-1,450, PEG-1,500,PEG-2,000, PEG-2,050, PEG-3,000, PEG-[3,000-3,700], PEG-3,350,PEG-4,000, PEG-4,600, PEG-6,000, PEG-8,000, PEG-10,000, PEG-12,000,PEG-20,000, PEG-35,000, and any mixtures thereof; the monoester of the(methyl vinyl ether-maleic acid) co-polymer is n-butyl, isopropyl,ethyl, or any mixtures thereof; the poloxamer comprises at least one ofpoloxamer 188, poloxamer 407, and any mixtures thereof.
 62. The methodof claim 60, wherein the composition comprises at least one of thefollowing: about 2% to about 20% w/w alcohol; about 5% to about 20.25%w/w polyol; about 5% to about 50% w/w organic solvent; about 2.5% w/worganic carbonate; about 1% to about 5% w/w fatty acid or a saltthereof; about 6% to about 78% w/w PEG; about 15% to about 20% w/wmonoester of a (methyl vinyl ether-maleic acid) co-polymer; about 5% toabout 15% w/w copolymer of PPG-12 and SMDI; about 2% w/w saccharine;about 15% to about 20% w/w PPG; about 1% to about 5% w/w poloxamer. 63.The method of claim 60, wherein the alcohol is ethanol, and wherein thecomposition comprises a % w/w ethanol concentration selected from thegroup consisting of: about 8.25%, about 10%, about 10.5%, about 12.5%,about 14.25%, about 15%, and about 20% w/w.
 64. The method of claim 60,wherein the composition comprises a % w/w 2-(2-ethoxyethoxy)-ethanolconcentration selected from the group consisting of about 5% and about10% w/w.
 65. The method of claim 60, wherein the composition comprises a% w/w polyol concentration selected from the group consisting of: about5%, about 8%, about 14.75%, about 15%, about 15.25% and about 20.25%w/w.
 66. The method of claim 60, wherein the composition comprises fromabout 10% to about 50% w/w organic solvent.
 67. The method of claim 57,wherein the composition comprises about 1% to about 5% w/w HPC.
 68. Themethod of claim 57, wherein the composition comprises a % w/w HPCconcentration selected from the group consisting of: about 1.75%, about2%, about 2.25%, about 2.5%, and about 5% w/w.
 69. The method of claim60, wherein the composition comprises about 3% w/w fatty acid or a saltthereof.
 70. The method of claim 60, wherein the composition comprises a% w/w PEG concentration selected from the group consisting of: about 6%,about 9%, about 10%, about 15%, about 18.25%, about 20%, about 20.5% andabout 78%.
 71. The method of claim 60, wherein the composition comprisesabout 20% w/w monoester of a (methyl vinyl ether-maleic acid)co-polymer.
 72. The method of claim 60, wherein the compositioncomprises about 10% w/w copolymer of PPG-12 and SMDI.
 73. The method ofclaim 60, wherein the composition is selected from the group consistingof: (a) about 28% w/w DMSO, about 10% w/w copolymer of PPG-12 and SMDI,about 2% w/w HPC, and about 60% w/w isoflurane; (b) about 25% w/w DMSO,about 5% w/w HPC, and about 70% w/w isoflurane; (c) about 3% w/w oleicacid, about 14.75% w/w propylene glycol, about 1.75% w/w HPC, about20.5% w/w PEG-400, and about 60% w/w isoflurane; (d) about 23% w/w DMSO,about 15% w/w PPG-400, about 2% w/w HPC, and about 60% w/w isoflurane;(e) about 8% w/w propylene glycol, about 2% w/w HPC, about 20% w/wisopropyl alcohol, and about 70% w/w isoflurane; (f) about 38.25% w/wDMSO, about 1.75 w/w HPC, and about 60% w/w isoflurane; (g) about 3% w/woleic acid, about 15% w/w propylene glycol, about 14.25% w/w ethanol,about 1.75% w/w HPC, about 1% w/w poloxamer 407, about 5% w/w poloxamer188, and about 60% w/w isoflurane; (h) about 10.5% w/w ethanol, about20% w/w monoester of a (methyl vinyl ether-maleic acid) co-polymer,about 2.5% w/w propylene carbonate, about 5% w/w2-(2-ethoxyethoxy)ethanol, about 2% w/w HPC, and about 60% w/wisoflurane; (i) about 35% w/w DMSO, about 5% w/w HPC, and about 60% w/wisoflurane; (j) about 3% w/w oleic acid, about 15.25% w/w propyleneglycol, about 10% w/w ethanol, about 1.75% w/w HPC, about 10% w/wPEG-400, and about 60% w/w isoflurane; (k) about 10% w/w copolymer ofPPG-12 and SMDI, about 8.25% w/w ethanol, about 20% w/w monoester of a(methyl vinyl ether-maleic acid) co-polymer, about 1.75% w/w HPC, andabout 60% w/w isoflurane; (l) about 10% w/w DMSO, about 5% w/w HPC, andabout 85% w/w isoflurane; (m) about 20% w/w DMSO, about 5% w/w HPC, andabout 75% w/w isoflurane; (n) about 3% w/w oleic acid, about 14.75% w/wpropylene glycol, about 2.25% w/w HPC, about 20% w/w PEG-400, and about60% w/w isoflurane; (o) about 3% w/w oleic acid, about 15% w/w propyleneglycol, about 2% w/w HPC, about 20% w/w PEG-400, and about 60% w/wisoflurane; (p) about 20% w/w monoester of a (methyl vinyl ether-maleicacid) co-polymer, about 1.75% w/w HPC, about 18.25% w/w PEG-400, andabout 60% w/w isoflurane; (q) about 18% w/w DMSO, about 20% w/wmonoester of a (methyl vinyl ether-maleic acid) co-polymer, about 2% w/wHPC, and about 60% w/w isoflurane; (r) about 5% w/w DMSO, about 5% w/wHPC, and about 90% w/w isoflurane; (s) about 3% w/w oleic acid, about10% w/w copolymer of PPG-12 and SMDI, about 15.25% w/w propylene glycol,about 10% w/w ethanol, about 1.75% w/w HPC, and about 60% w/wisoflurane; (t) about 37.5% w/w DMSO, about 2.5% w/w HPC, and about 60%w/w isoflurane; and (u) about 3% w/w oleic acid, about 20.25% w/wpropylene glycol, about 15% w/w ethanol, about 1.75% w/w HPC, and about60% w/w isoflurane.
 74. The method of claim 57, wherein the compositionis incorporated in a medical patch.
 75. A method of reducing orameliorating pain in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of auniform composition comprising a halogenated volatile compound and amonoester of a (methyl vinyl ether-maleic acid) co-polymer; wherein thehalogenated volatile compound is selected from the group consisting ofisoflurane, halothane, enflurane, sevoflurane, desflurane,methoxyflurane, and any mixtures thereof.
 76. The method of claim 75,wherein the composition comprises about 5% to about 95% w/w halogenatedvolatile compound.
 77. The method of claim 75, wherein the compositioncomprises about 50% to about 90% w/w halogenated volatile compound. 78.The method of claim 75, wherein the composition further comprises atleast one selected from the group consisting of an alcohol; a polyol; anorganic solvent; an organic carbonate; a fatty acid or a salt thereof; apolyethylene glycol (PEG); a polypropylene glycol (PPG); a copolymer of2-(2-hydroxypropoxy)propan-1-ol (PPG-12) and 1-methylenebis-4-isocyanatocyclohexane (SMDI); a poloxamer; saccharine;2-(2-ethoxyethoxy)-ethanol; hydroxypropyl cellulose (HPC); and anycombinations thereof; wherein the polyol is selected from the groupconsisting of ethylene glycol, propylene glycol, glycerol, and anymixtures thereof, wherein the organic solvent is selected from the groupconsisting of dimethylsulfoxide (DMSO), dimethylisosorbide, and anymixtures thereof, and wherein the organic carbonate is selected from thegroup consisting of propylene carbonate, ethylene carbonate and anymixtures thereof.
 79. The method of claim 78, wherein at least oneapplies: the alcohol is selected from the group consisting of methanol,ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol,t-butanol, and any mixtures thereof; the fatty acid or salt thereof isselected from the group consisting of myristoleic acid, palmitoleicacid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleicacid, linoelaidic acid, α-linolenic acid, arachidonic acid,eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid,capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,arachidic acid, behenic acid, lignoceric acid, cerotic acid, and anycombinations thereof; the PEG is selected from the group consisting ofPEG-200, PEG-300, PEG-400, PEG-600, PEG-[950-1,050], PEG-1,000,PEG-[1,300-1,600], PEG-[1,305-1,595], PEG-1,450, PEG-1,500, PEG-2,000,PEG-2,050, PEG-3,000, PEG-[3,000-3,700], PEG-3,350, PEG-4,000,PEG-4,600, PEG-6,000, PEG-8,000, PEG-10,000, PEG-12,000, PEG-20,000,PEG-35,000, and any mixtures thereof; the poloxamer comprises at leastone of poloxamer 188, poloxamer 407, and any mixtures thereof.
 80. Themethod of claim 78, wherein the composition comprises at least one ofthe following: about 2% to about 20% w/w alcohol; about 5% to about20.25% w/w polyol; about 5% to about 50% w/w organic solvent; about 2.5%w/w organic carbonate; about 1% to about 5% w/w fatty acid or a saltthereof; about 6% to about 78% w/w PEG; about 5% to about 15% w/wcopolymer of PPG-12 and SMDI; about 2% w/w saccharine; about 15% toabout 20% w/w PPG; about 1% to about 5% w/w poloxamer; about 1% to about5% w/w HPC
 81. The method of claim 78, wherein the alcohol is ethanol,and wherein the composition comprises a % w/w ethanol concentrationselected from the group consisting of: about 8.25%, about 10%, about10.5%, about 12.5%, about 14.25%, about 15%, and about 20% w/w.
 82. Themethod of claim 78, wherein the composition comprises a % w/w2-(2-ethoxyethoxy)-ethanol concentration selected from the groupconsisting of about 5% and about 10% w/w.
 83. The method of claim 78,wherein the composition comprises a % w/w polyol concentration selectedfrom the group consisting of: about 5%, about 8%, about 14.75%, about15%, about 15.25% and about 20.25% w/w.
 84. The method of claim 78,wherein the composition comprises from about 10% to about 50% w/worganic solvent.
 85. The method of claim 78, wherein the compositioncomprises a % w/w HPC concentration selected from the group consistingof: about 1.75%, about 2%, about 2.25%, about 2.5%, and about 5% w/w.86. The method of claim 78, wherein the composition comprises about 3%w/w fatty acid or a salt thereof.
 87. The method of claim 78, whereinthe composition comprises a % w/w PEG concentration selected from thegroup consisting of: about 6%, about 9%, about 10%, about 15%, about18.25%, about 20%, about 20.5% and about 78%.
 88. The method of claim75, wherein the monoester of the (methyl vinyl ether-maleic acid)co-polymer is n-butyl, isopropyl, ethyl, or any mixtures thereof. 89.The method of claim 75, wherein the composition comprises about 15% toabout 20% w/w monoester of (methyl vinyl ether-maleic acid) co-polymer.90. The method of claim 75, wherein the composition comprises about 20%w/w monoester of (methyl vinyl ether-maleic acid) co-polymer.
 91. Themethod of claim 78, wherein the composition comprises about 10% w/wcopolymer of PPG-12 and SMDI.
 92. The method of claim 78, wherein thecomposition is selected from the group consisting of: (a) about 12.5%w/w ethanol, about 20% w/w monoester of a (methyl vinyl ether-maleicacid) co-polymer, about 2.5% w/w propylene carbonate, about 5% w/w2-(2-ethoxyethoxy)ethanol, and about 60% w/w isoflurane; (b) about 10.5%w/w ethanol, about 20% w/w monoester of a (methyl vinyl ether-maleicacid) co-polymer, about 2.5% w/w propylene carbonate, about 5% w/w2-(2-ethoxyethoxy)ethanol, about 2% w/w HPC, and about 60% w/wisoflurane; (c) about 10% w/w copolymer of PPG-12 and SMDI, about 8.25%w/w ethanol, about 20% w/w monoester of a (methyl vinyl ether-maleicacid) co-polymer, about 1.75% w/w HPC, and about 60% w/w isoflurane; (d)about 20% w/w monoester of a (methyl vinyl ether-maleic acid)co-polymer, about 1.75% w/w HPC, about 18.25% w/w PEG-400, and about 60%w/w isoflurane; (e) about 18% w/w DMSO, about 20% w/w monoester of a(methyl vinyl ether-maleic acid) co-polymer, about 2% w/w HPC, and about60% w/w isoflurane;
 93. The method of claim 75, wherein the compositionis incorporated in a medical patch.